Method for the treatment of acne

ABSTRACT

A method for treatment of acne with tetracyclines is provided. A lower sustained dose and no loading dose is employed, with an optional once-a-day dosing regimen.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/166,817 filed on Jun. 24, 2005 the entire disclosure of which isincorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to the treatment of acne vulgaris, commonly knownsimply as “acne.” Acne is a disease of the skin in which thepilosebaceous structures of the skin become inflamed, leading to theformation of comedones, pustules and nodules. Acne can lead to permanentscarring in severe cases.

It is generally believed that acne arises when hyperkeratosis of thepilosebaceous structure wholly or partially blocks the opening of thestructure, resulting in comedones filled with sebum, keratin, andPropionibacterium acnes. These lesions are commonly identified as acne.P. acnes naturally occurs in normal skin, but is especially andcharacteristically present in acne lesions. It is believed thatmetabolic byproducts and waste from P. acnes within the pilosebaceousstructures cause or contribute to the inflammation of acne lesions.

Conventional acne treatments have taken many forms. Topical keratolyticagents, such as salicylic acid are sometimes used. Keratolytic agentsare thought to encourage the opening up of blocked pilosebaceousstructures, thereby reducing conditions that are favorable toinflammation. Benzoyl peroxide, an anti-microbial, remains a popular andeffective treatment. Topical antibiotics, such as clindamycin, which areeffective against P. acnes, have also been used with a view towardspreventing the formation of metabolic byproducts from this organism.Topical retinoids such as tretinoin have also been used in the treatmentof acne.

Systemic (i.e. non-topical) treatments for acne include the use of oralantibiotics in more serious cases. These treatments are directed towardsthe reduction in the amount P. acnes in the skin, especially thepilosebaceous structures, and seek to reduce the inflammation caused bywaste materials and metabolic byproducts from these organisms.Tetracycline antibiotics are most commonly used for this purpose. Theseinclude tetracycline, minocycline and doxycycline. Erythromycin is alsosometimes used.

Standard oral minocycline therapy for acne in pediatric patients callsfor the administration of a 4 mg/kg initial loading dose, and a 2 mg/kgdose every 12 hours thereafter. This results in a dose of 6 mg/kg on thefirst day of treatment and a 4 mg/kg dose each day thereafter. Inadults, a 200 mg initial dose is followed by a 100 mg dose every 12hours thereafter. In a typical patient, this results in about a 4.5mg/kg dose on the first day of treatment, and 3.0 mg/kg dose each daythereafter.

In cases where acne does not respond to oral antibiotic treatment, oralisotretinoin is sometimes used. While effective, isotretinoin is alsopowerfully teratogenic, and women of childbearing age are required touse multiple methods of contraception while taking the drug.

While oral tetracycline antibiotics remain a highly favored and widelyused treatment for more serious cases of acne, it is not without sideeffects. Vestibular side effects, including extreme dizziness andconcomitant nausea, can be so severe as to result in discontinuance oftetracycline therapy. Long term use can sometimes result in vaginalcandidisis, esophageal erosions and in antibiotic resistant infections.

Some recent research has indicated that very low doses of oraltetracycline can result in some improvement of acne even though the doseof tetracycline is too low to have an antibiotic effect. Thisobservation has been attributed to an anti-inflammatory effect oftetracycline compounds. This effect has been reported to have beenobserved even where a chemically modified tetracycline that have noantibiotic properties are used. The use of tetracycline antibiotics at adose too low to have an antibiotic effect or the use of modifiedtetracycline having no antibiotic properties as treatments for acne hasnever been approved by any drug regulatory agency.

SUMMARY OF THE INVENTION

According to the present invention, a method is provided for thetreatment of acne in which an antibiotically effective dose of an oraltetracycline, such as minocycline, is provided. This dose isapproximately 1 milligram per kilogram of body weight (1 mg/kg), withoutan initial loading dose of antibiotic. This antibiotic dosing regimenhas been found to be as effective as a conventional dosing regimenincorporating a significant initial loading dose and higher subsequentdoses. However, the dosing method of the current invention produces farfewer side effects.

In another aspect of this invention, the oral tetracycline is providedin a dosage form that provides for the continued release of theantibiotic between doses, as opposed to an immediate or nearly immediaterelease of the drug.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, acne vulgaris is treated by the useof an oral tetracycline antibiotic, preferably minocycline. Thisantibiotic is administered in an antibiotically effective amount ofapproximately 1.0 milligram per kilogram of body weight per day (1.0mg/kg/day). While this may be accomplished by the use of divided doses,it is preferred that the tetracycline antibiotic be delivered in asingle daily dose. This treatment regime is initiated without a loadingdose, and is continued until resolution or substantial resolution of thepatient's acne. The course of treatment typically lasts 12 to up to 60weeks, but will be adjusted according to the disease status and othermedical conditions of each patient in the exercise of ordinary goodclinical judgment by the patient's health care provider.

Controlled, double-blinded studies were undertaken to determine theeffectiveness of this invention. Treatment of 473 patients with acne wasundertaken according to the present invention. Placebos were provided to239 patients. The effectiveness of the invention in treating acnevulgaris is shown in Table 1. TABLE 1 Total Lesion Counts Total TotalLesions Lesions (as Percent of Baseline) Baseline (mean) 169.3 100 Day28 (mean) 134.0 78 Day 56 (mean) 119.3 69 Day 84 (mean) 112.3 66Inflammatory Lesion Counts Inflammatory Inflammatory Lesions Lesions (asPercent of Baseline) Baseline (mean) 77.4 100 Day 28 (mean) 52.1 66 Day56 (mean) 44.3 56 Day 84 (mean) 41.9 53

While effective as a treatment for acne, this resulted in almost no sideeffects above those observed with a placebo, as shown in Table 2. TABLE2 % Subjects with Adverse Events Minocycline Placebo At least OneAdverse Event 56.2 54.1 At Least One Serious Adverse Event 0.4 0Blood/Lymphatic System Disorders 0.3 0.3 Cardiac Disorders 0.3 0 Ear andLabyrinth Disorders 3.6 3.3 Endocrine Disorders 0.3 0 Eye Disorders 2.22.7 Gastrointestinal Disorders 21.2 26.1 General Disorders andAdministrative 13.8 10.4 Site Conditions Immune System Disorders 0.7 2.5Infections and Infestations 9.3 11.0 Laboratory Blood Abnormalities 0.71.1 Metabolism and Nutrition Disorders 0.6 0.3 Musculoskeletal andConnective 4.6 3.6 Disorders Neoplasms Benign, Malignant and 0.1 0Unspecified Nervous System Disorders 29.2 25.8 Psychiatric Disorders 6.47.1 Renal and Urinary Disorders 0.3 0.5 Reproductive System and Breast0.7 0.3 Disorders Respiratory, Thoracic and Mediastinal 5.3 6.9Disorders Skin and Subcutaneous Tissue Disorders 8.6 7.1 VascularDisorders 1.0 0.3

The effectiveness of this invention can be seen by comparing the aboveefficacy data with published data on the effectiveness of conventionaltetracycline treatments for acne in the reduction of total acne lesionsand in the reduction of inflammatory lesions. See, e.g. Hersel &Gisslen, “Minocycline in Acne Vulgaris: A Double Blind Study,” CurrentTherapeutic Research, 1976.

Because of the variations in body weight encountered in clinicalpractice, in the actual practice of this invention it is not practicalto provide every patient with exactly 1 mg/kg/day of oral tetracyclineantibiotic. However, it is acceptable to approximate this dose byproviding the patient with from 0.5 to 1.5 mg/kg/day although from 0.7to 1.3 mg/kg/day is preferred, and 1.0 mg/kg/day is ideal.

While it can be effective to provide the oral tetracycline antibiotic individed doses taken over the course of a day (e.g. twice or three timesa day), it is preferable to provide the oral tetracycline antibiotic ina dosage form that releases the antibiotic slowly during the course of aday so that once-a-day dosing is possible. While delayed release dosageforms are known in the art, the formulation of them is far frompredictable and the selection of a specific delayed release formulationis accomplished more by trial and error than by mathematical predictionbased on known properties of delay release agents. No delayed releaseproduct useful in the present invention has been known heretofore.

It has been discovered that the ratio of fast dissolving carriers toslow dissolving carriers in the core caplet is important in obtaining adissolution profile that enables once-a-day dosing in accordance withthe present invention. By keeping the ratio of these components within acertain range, one may obtain this result.

The fast dissolving carrier is any binder, vehicle, or excipient thatquickly dissolves in an aqueous physiological medium, such as gastricfluid, thereby tending to quickly release the active ingredient.Lactose, its salts and hydrates are good examples of such components. Ithas been observed that sometimes a portion of the fast dissolvingcomponents are formulated in a manner that results in the complete orpartial encapsulation or inclusion or coating of these fast-dissolvingmaterials in granules of slow-dissolving materials. These encapsulatedmaterials are excluded from the calculation of the above mentioned ratioof fast-dissolving to slow dissolving components.

A slow dissolving carrier is any binder, vehicle, or excipient thatdissolves slowly over the course of hours and perhaps a day, therebyslowing the release of the active ingredient. Examples of suchcomponents are polyvinyl pyrrolidone, polyvinyl acetate,microcrystalline cellulose, methyl cellulose, ethyl cellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or waxy orlipid-based tableting agents such as magnesium stearate or calciumstearate. Outer “enteric” coatings are excluded from this amount whencalculating the above-mentioned ratio.

Insoluble carriers are binders, vehicles, or excipients that arepractically insoluble in physiological fluids, such as gastric fluid,and includes compounds, such as silicon dioxide and talc.

While the exact formulation of these dosage forms can vary, it has beenobserved that it is advantageous to formulate them so that the ratio offast dissolving carriers to slow dissolving carriers is from 0.30 to0.50, and preferably from 0.35 to 0.45. A ratio of about 0.36 to 0.40 isparticularly preferable.

Dosage forms, such as capsules, tablets, and caplets that release 25 to52 % of the antibiotics within 1 hour, 53 to 89 % in 2 hours, and atleast 90 % within 4 hours are suited to the once-a-day dosage regimencontemplated by the current inventories. More preferably, 30 to 52 % ofthe antibiotic is released within 1 hour, 53 to 84 % within 2 hours, andat least 85 % within 4 hours.

Alternatively, the oral tetracycline antibiotic may be delivered in adosage form that releases the antibiotic in such a way that the maximumblood concentration of the antibiotic (C_(max)) is reached at about 3.5hours after administration (T_(max)). In actual practice of theinvention, the C_(max) should be reached between 2.75 and 4.0 afteradministration, more preferably between 3.0 and 3.75 afteradministration.

As examples of such a once-a-day formulation, one may use the following:Component Quantity (mg) 135 mg Caplet Minocycline (as hydrochloride)(dry weight) 145.8 Lactose Monohydrate (intragranular) 107.4 LactoseMonohydrate (extragranular) 43.8 Total Lactose Monohydrate 151.2 HPMC 94Silicon Dioxide 3 Mg. Stearate 6 45 mg Caplet Minocycline (ashydrochloride) (dry weight) 48.6 Lactose Monohydrate (intragranular)192.2 Lactose Monohydrate (extragranular) 42.2 Total Lactose Monohydrate234.40 HPMC 108 Silicon Dioxide 3 Mg. Stearate 6

Each of these components is combined in a conventional fashion,compressed in a tabletting apparatus, and then provided in aconventional manner with a suitable coating, such as, without limitationOpadry II and optional coloring.

1. A method of preparing an oral dosage form, comprising combining anoral minocycline antibiotic with a fast dissolving carrier and a slowdissolving carrier to form a combination, wherein said fast dissolvingcarrier and said slow dissolving carrier are at a weight ratio of about0.3 to about 0.5 of fast dissolving carrier to slow dissolving carrier.2. The method of claim 1, wherein said oral minocycline antibiotic isminocycline as hydrochloride.
 3. The method of claim 1, wherein theweight ratio of fast dissolving carrier to slow dissolving carrier isabout 0.35 to about 0.45.
 4. The method of claim 1, wherein the weightratio of fast dissolving carrier to slow dissolving carrier is about0.36 to about 0.40.
 5. The method of claim 1, wherein said fastdissolving carrier comprises lactose monohydrate.
 6. The method of claim1, wherein said slow dissolving carrier comprises HPMC.
 7. The method ofclaim 1, wherein: said fast dissolving carrier comprises lactosemonohydrate; and said slow dissolving carrier comprises HPMC.
 8. Themethod of claim 1, wherein said slow dissolving carrier is present atabout 23.5 to about 27.0% by weight of the oral dosage form.
 9. Themethod of claim 1, wherein said slow dissolving carrier is present at:23.5% by weight of said oral dosage form when said oral dosage formcomprises 135 mg of said oral minocycline antibiotic; or 27.0% by weightof said oral dosage form when said oral dosage form comprises 45 mg ofsaid oral minocycline antibiotic.
 10. The method of claim 1, furthercomprising compressing said combination into a tablet.
 11. The method ofclaim 1, wherein said oral dosage form is formulated to provide apatient with about 0.5 mg/kg/day to about 1.5 mg/kg/day of said oralminocycline antibiotic.